The long-term goal of this project is to relate specific immune responses to infectious diseases to subsequent neurologic and neuropsychologic deficits. The objectives of the present proposal are to establish the infrastructure and trained personnel to conduct such studies and to generate preliminary data on the relationship between serum IL-10 and TNF-c_ levels and neurologic and neuropsychologic deficits in children with cerebral malaria (CM). Malaria is the leading cause of death in children under 5 years of age in Uganda. CM is known to be a leading cause of malaria- related mortality in Uganda, but morbidity from CM, particularly the effect of CM on cognitive function, has not been well characterized. We propose to assess the general incidence of CM in Uganda through retrospective chart review and a prospective study categorizing malaria-related disease (e.g. CM, severe malarial anemia) in all individuals admitted with malaria at Mulago Hospital, Kampala and Kabale Hospital, Kabale. We then propose to study the relationships between CM, immune responses to this condition and neurologic and neuropsychologic sequelae in a multi-disciplinary collaboration of physicians, developmental specialists and scientists from Case Western Reserve University (CWRU), Indiana Wesleyan University and Makerere University, Uganda. The long-standing collaboration between CWRU and Makerere University in the areas of tuberculosis and HIV research and the well-equipped immunology laboratory shared by these institutions will facilitate the performance of this project. The project will have a training component with both group education and individual training modules and an infrastructure component with support for testing equipment, supplies and simple renovation of spaces for clinical assessment and data management. The training modules will include a core curriculum for all study personnel and trainees with courses in clinical areas (malaria pathogenesis; care of the acutely ill child; neurologic examination), neuropschology (assessment of child cognition and development), immunology (host defense and infection, principles of laboratory immunology) and ethics in scientific research. In addition to the core curriculum, individual study personnel and trainees will receive hands-on training in the above areas as appropriate to their role in the study. In the second year of the study, courses in study design and scientific writing will be given for senior personnel. Infrastructure improvement will focus on dedicated clinical and office space and computing facilies for a Center for Cerebral Malaria Research that will support the proposed research. Trained personnel will undertake a pilot study in which serum IL-10 and TNF-_ levels are compared in children with and without CM and then compared to neuropsychological and neurologic parameters in children with CM at the time of discharge, and 1, 3, and 12 months later. This preliminary data will be the foundation for future studies investigating a broader range of antecedent immune factors in CM and neurologic and cognitive function. PERFORMANCESITE(S) (organization,city, state) Case Western Reserve University, Cleveland, Ohio Indiana Wesleyan Univeristy, Marion, Indiana Kabale Regional Referral Center, Kabale, Uganda Makerere University and Mulago Hospital, Kampala, Uganda KEY PERSONNEL. See instructions. Use continuation pages as neededto providethe required information in the format shown below. Start with Principal Investigator.List all other key personnel in alphabetical order, last namefirst. Name Organization Role on Project Chandy C. John Case Western Reserve University Principal Investigator Edward Bitarakwate Kabale Regional Referral Hospital Consultant Michael Boivin Indiana Wesleyan University Co-investigator Justus Byarugaba Makerere University Consultant Richard Idro Makerere University Co-Principal Investigator Karen Olness Case Western Reserve University Collaborator Burton Webb Indiana Wesleyan University Consultant DisclosurePermissionStatement. Applicable to SBIR/STTR Only. See instructions. [] Yes [] No Page 2 Principal Investigator/Program Director (Last, first, middle): John, Chandy C. The name of the principal investigator/program director must be provided at the top of each printed page and each continuation page. RESEARCH GRANT TABLE OF CONTENTS Page Numbers Face Page .................................................................................................................................................. 1 Description,